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Diacerein for osteoarthritis

What is osteoarthritis and what is diacerein?

Osteoarthritis (OA) is the most common form of arthritis. In OA, the cartilage that protects the ends of the bones breaks down, causing pain and swelling. OA can affect any joint, but the knees, hips and hands are the joints most often studied in clinical trials. In all, 10% of the world’s population aged 60 or older have pain or disability from OA.

Diacerein is a slow-acting drug taken as a pill that may slow the breakdown of cartilage and relieve pain and swelling.

The review searched for studies up to March 2013 about primary osteoarthritis affecting men and women (18 years and older) of any disease severity.

The review shows that in people with osteoarthitis:

- Pain may improve slightly more in people taking diacerein.

- Improvement in physical function is about the same for people taking diacerein,- or a placebo (fake pill). This may have happened by chance.

- Diacerein may slow the process of joint space narrowing slightly of the hip but may have little or no difference on the knee joint as it is seen on an x-ray.

- Diacerein may cause side effects in the lower digestive tract, such as diarrhoea.

Further research is very likely to have an important impact on our confidence in these findings and is likely to change the estimates.

Best estimate of what happens to people with osteoarthritis who take diacerein

Pain after three to 36 months

- People who took diacerein rated their pain to be 9 points lower on a scale of 0 (no pain) to 100 (extreme pain) after taking the medication for three to 36 months (9% absolute improvement).

- People who took diacerein rated their pain to be 34 on a scale of 0 to 100 after taking the medication compared to people who took a fake pill and rated their pain to be 43 points on a scale of 0 to 100.

- People who took diacerein rated their physical function to be 0.30 points lower on a scale of 0 to 24 after taking the medication for two to 36 months (0% absolute improvement).

- People who took diacerein rated their physical function to be 9.3 on a scale of 0 to 24 after taking the medication compared to people who took a fake pill and rated their physical function to be 9 points on a scale of 0 to 24.

Radiographic progression - how the joint looks on an x-ray (reduction in joint space narrowing of at least 0.5 mm)

- Seven more people who took placebo had radiographic progression (absolute difference of 7%).

- 42 of every 100 people who took diacerein experienced reduction in joint space narrowing of at least 0.5 mm compared to 49 of every 100 people who took a fake pill.

Quality of life

- The review authors found no studies about quality of life of people who took diacerein compared with placebo.

- There was no difference in quality of life of people who took diacerein compared with non-steroidal anti-inflammatory drugs (NSAIDs). This may have happened by chance.

Side effects

- Twenty-six more people who took diacerein experienced diarrhoea as a side effect (absolute difference of 26%).

- 36 of every 100 people who took diacerein experienced diarrhoea as a side effect compared to 10 of every 100 who took a fake pill.

Diarrhoea was the most common side effect and usually occurred during the first two weeks after the start of diacerein.

People who took diacerein were not more likely than people who took a placebo to stop taking the medication because of side effects.

In November 2013, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) recommended that the marketing authorisation of diacerein should be suspended across Europe because of harms outweighing benefits. However, this guidance is not final as the PRAC recommendation will be re-examined.

Authors' conclusions:

In this update, the strength of evidence for effectiveness outcomes was low to moderate. We confirmed that symptomatic benefit provided by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip. With respect to adverse effects of diacerein, diarrhoea was most frequent. Given the recent guidance issued by the EMA recommending suspension of diacerein in Europe, the EMA website should be consulted for further recommendations regarding the use of diacerein.

Read the full abstract...

Background:

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. There is currently no consensus on what is the best treatment to improve OA symptoms and slow disease progression. Diacerein is an anthraquinone synthesised in 1980 that interferes with interleukin-1, an inflammatory mediator. It has been proposed that diacerein acts as a slow-acting, symptom-modifying and perhaps disease-structure-modifying drug for OA. This is an update of a Cochrane review first published in 2006.

Objectives:

To assess the benefits and harms of diacerein for the treatment of adults with OA when compared with placebo and other pharmacologically active interventions (nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptom-modifying, slow-acting drugs) for OA.

Search strategy:

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library, Issue 10, 2013, MEDLINE (1966 to 2013), EMBASE (1980 to 2013), LILACS (1982 to 2013), and ACP Journal Club, and we handsearched reference lists of published articles. We also searched the World Health Organization International Clinical Trials Platform ( http://www.who.int/trialsearch/Default.aspx) to identify ongoing trials and screened reference lists of retrieved review articles and trials to identify potentially relevant studies. All searches were up to date as of March 2013. Pharmaceutical companies and authors of published articles were contacted. We searched the websites of the regulatory agencies using the keyword ‘diacerein’ in November 2013. No language restrictions were applied.

Selection criteria:

Studies were included if they were randomised or quasi-randomised controlled trials that compared diacerein with placebo or another active pharmacological intervention in participants with OA.

Data collection and analysis:

Data abstraction and quality assessment were performed by two independent investigators, and their results were compared. The Cochrane risk of bias tool was used. The quality of evidence obtained was assessed using the GRADE approach.

Main results:

We identified three new trials (141 participants), and this updated review now includes 10 trials, totalling 2,210 participants. The most frequent risk of bias was incomplete outcomedata, identified in approximately 80% of the studies. Allocation concealment and random sequence generation were unclear in 90% and 40% of the studies, respectively, because of poor reporting.

Low-quality evidence from six trials (1,283 participants) indicates that diacerein has a small beneficial effect on overall pain (measured on a 100 mm visual analogue scale) at three to 36 months (mean difference (MD) -8.65, 95% confidence interval (CI) -15.62 to -1.68), which is equivalent to a 9% pain reduction in the diacerein group (95% CI -16% to -2%) compared with the placebo group. This benefit may not be clinically significant.

Low-quality evidence from two trials (616 participants) on slowing of joint space narrowing (a decrease greater than 0.50 mm) in the knee or hip favoured diacerein over placebo (risk ratio (RR) 0.85, 95% CI 0.72 to 0.99), with an absolute risk difference of -6% (95% CI -15% to 2%) and a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 8 to 203). Analysis of the knee joint alone (1 study, 170 participants) did not reach statistical significance (RR 0.94, 95% CI 0.51 to 1.74).

None of the trials of diacerein versus placebo measured quality of life. According to one trial (161 participants), which compared diacerein versus non-steroidal anti-inflammatory drugs (NSAIDs), the quality of life of participants in the two groups (as assessed by the Short Form (SF)-36 health survey questionnaire (0 to 800 sum score)) did not differ significantly (MD -40.70, 95% CI -85.20 to 3.80).

Low-quality evidence from seven trials showed significantly more adverse events in the diacerein group compared with the placebo group after two to 36 months, mainly diarrhoea (RR 3.52, 95% CI 2.42 to 5.11), with an absolute risk increase of 24% (95% CI 12% to 35%), and a number needed to treat for an additional harmful outcome (NNTH) of 4 (95% CI 3 to 7).

No statistically significant differences in participant withdrawal due to adverse events were seen at two to 36 months for diacerein compared with placebo (RR 1.29, 95% CI 0.83 to 2.01).

A search of regulatory websites found a recommendation from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) that the marketing authorization of diacerein should be suspended across Europe because of harms (particularly the risk of severe diarrhoea and potentially harmful effects on the liver) outweighing benefits. However, this guidance is not final as the PRAC recommendation will be re-examined.

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